Medical Microbiology

ImmuneResponsesandEffectorMechanisms 73

T-CellActivation

Fig.2. 11 RegulationofT-cellactivationiscontrolledbymultiplesignals,including

costimulatorysignals(Signal2).StimulationoftheTcellviatheT-cellreceptor

(TCR;Signal1)activatesatyrosinekinase,whichinturnactivatesphospholipase

C(PLC).PLCsplitsphosphatidylinositolbisphosphate(PIP 2 )intoinositoltrispho-

sphate(IP 3 )anddiacylglycerol(DAG).IP 3 releasesCa2+fromintracellulardepots,

whilstDAGactivatesproteinkinaseC(PKC).Together,Ca2+andPKCinduceand

activatethephosphoproteinsrequiredforIL-2genetranscriptionwithinthecell

nucleus.StimulationofaTcellviatheTCRaloneresultsinproductionofonly

verysmallamountsofIL-2.IncreasedIL-2productionoftenrequiresadditionalsig-

nals(costimulation,e.g.,viaCD28).CostimulationviaCD28activatestyrosineki-

nases,whichbothsustainthetranscriptionprocessandensurepost-transcriptional

stabilizationofIL-2mRNA.Immunosuppressivesubstances(inredletters)include

cytostaticdrugs,anti-TCR,anti-CD3,anti-CD28(CTLA4),anti-CD40,cyclosporine

AandFK506(whichinterfereswithimmunophilin-calcineurinbinding,thusreduc-

ingIL-2production),andrapamycin(whichbindsto,andblocks,immunophilin

andhardlyreducesIL-2atall).Anti-interleukins(especiallyanti-IL-2,oracombina-

tionofanti-IL-2receptorandanti-IL-15)blockT-cellproliferation.

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Kayser, Medical Microbiology © 2005 Thieme